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Chapter 23

Chapter 23. Gluconeogenesis. Glycogen Metabolism, and the Pentose Phosphate Pathway to accompany Biochemistry, 2/e by Reginald Garrett and Charles Grisham.

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Chapter 23

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  1. Chapter 23 Gluconeogenesis. Glycogen Metabolism, and the Pentose Phosphate Pathway to accompany Biochemistry, 2/e by Reginald Garrett and Charles Grisham All rights reserved. Requests for permission to make copies of any part of the work should be mailed to: Permissions Department, Harcourt Brace & Company, 6277 Sea Harbor Drive, Orlando, Florida 32887-6777

  2. Outline • 23.1 Gluconeogenesis • 23.2 Regulation of Gluconeogenesis • 23.4 Glycogen Synthesis • 23.5 Control of Glycogen Metabolism

  3. Gluconeogenesis Synthesis of "new glucose" from common metabolites • Humans consume 160 g of glucose per day • 75% of that is in the brain • Body fluids contain only 20 g of glucose • Glycogen stores yield 180-200 g of glucose • So the body must be able to make its own glucose

  4. Substrates for Gluconeogenesis Pyruvate, lactate, glycerol, amino acids and all TCA intermediates can be utilized • Fatty acids cannot! • Why? • Most fatty acids yield only acetyl-CoA • Acetyl-CoA (through TCA cycle) cannot provide for net synthesis of sugars

  5. Gluconeogenesis I • Occurs mainly in liver and kidneys • Not the mere reversal of glycolysis for 2 reasons: • Energetics must change to make gluconeogenesis favorable (delta G of glycolysis = -74 kJ/mol • Reciprocal regulation must turn one on and the other off - this requires something new!

  6. Gluconeogenesis II Something Borrowed, Something New • Seven steps of glycolysis are retained: • Steps 2 and 4-9 • Three steps are replaced: • Steps 1, 3, and 10 (the regulated steps!) • The new reactions provide for a spontaneous pathway (G negative in the direction of sugar synthesis), and they provide new mechanisms of regulation

  7. Pyruvate Carboxylase Pyruvate is converted to oxaloacetate • The reaction requires ATP and bicarbonate as substrates • That should make you think of biotin! • Biotin is covalently linked to an active site lysine • Acetyl-CoA is an allosteric activator • The mechanism (Figure 23.4) is typical of biotin! • Regulation: when ATP or acetyl-CoA are high, pyruvate enters gluconeogenesis • Note the "conversion problem" in mitochondria

  8. PEP Carboxykinase Conversion of oxaloacetate to PEP • Lots of energy needed to drive this reaction! • Energy is provided in 2 ways: • Decarboxylation is a favorable reaction • GTP is hydrolyzed • GTP used here is equivalent to an ATP

  9. Fructose-1,6-bisphosphatase Hydrolysis of F-1,6-P to F-6-P • Thermodynamically favorable - G in liver is -8.6 kJ/mol • Allosteric regulation: • citrate stimulates • fructose-2,6--bisphosphate inhibits • AMP inhibits

  10. Glucose-6-Phosphatase Conversion of Glucose-6-P to Glucose • Presence of G-6-Pase in ER of liver and kidney cells makes gluconeogenesis possible • Muscle and brain do not do gluconeogenesis • G-6-P is hydrolyzed as it passes into the ER • ER vesicles filled with glucose diffuse to the plasma membrane, fuse with it and open, releasing glucose into the bloodstream.

  11. Lactate Recycling How your liver helps you during exercise.... • Recall that vigorous exercise can lead to a buildup of lactate and NADH, due to oxygen shortage and the need for more glycolysis • NADH can be reoxidized during the reduction of pyruvate to lactate • Lactate is then returned to the liver, where it can be reoxidized to pyruvate by liver LDH • Liver provides glucose to muscle for exercise and then reprocesses lactate into new glucose

  12. Regulation of Gluconeogenesis Reciprocal control with glycolysis • When glycolysis is turned on, gluconeogenesis should be turned off • When energy status of cell is high, glycolysis should be off and pyruvate, etc., should be used for synthesis and storage of glucose • When energy status is low, glucose should be rapidly degraded to provide energy • The regulated steps of glycolysis are the very steps that are regulated in the reverse direction!

  13. Gluconeogenesis Regulation II Allosteric and Substrate-Level Control • See Figure 23.11 • Glucose-6-phosphatase is under substrate-level control, not allosteric control • The fate of pyruvate depends on acetyl-CoA • F-1,6-bisPase is inhibited by AMP, activated by citrate - the reverse of glycolysis • Fructose-2,6-bisP is an allosteric inhibitor of F-1,6-bisPase

  14. 23.4 Glycogen Synthesis - I Glucose units are activated for transfer by formation of sugar nucleotides • What are other examples of "activation"? • acetyl-CoA, biotin, THF, • Leloir showed in the 1950s that glycogen synthesis depends on sugar nucleotides • UDP-glucose pyrophosphorylase - Fig. 23.18 • a phosphoanhydride exchange • driven by pyrophosphate hydrolysis

  15. Glycogen Synthase Forms -(1 4) glycosidic bonds in glycogen • Glycogenin (a protein!) forms the core of a glycogen particle • First glucose is linked to a tyrosine -OH • Glycogen synthase transfers glucosyl units from UDP-glucose to C-4 hydroxyl at a nonreducing end of a glycogen strand. • Note another oxonium ion intermediate (Fig. 23.19)

  16. 23.5 Control of Glycogen Metabolism A highly regulated process, involving reciprocal control of glycogen phosphorylase and glycogen synthase • GP allosterically activated by AMP and inhibited by ATP, glucose-6-P and caffeine • GS is stimulated by glucose-6-P • Both enzymes are regulated by covalent modification - phosphorylation

  17. Phosphorylation of GP and GS Covalent control • Edwin Krebs and Edmond Fisher showed in 1956 that a "converting enzyme" converted phosphorylase b to phosphorylase a(P) • Phosphorylation causes the amino terminus of the protein (res 10-22) to swing through 120 degrees, moving into the subunit interface and moving Ser-14 by more than 3.6 nm • Nine Ser residues on GS are phosphorylated!

  18. Enzyme Cascades and GP/GS Hormonal regulation • Hormones (glucagon, epinephrine) activate adenylyl cyclase • cAMP activates kinases and phosphatases that control the phosphorylation of GP and GS • GTP-binding proteins (G proteins) mediate the communication between hormone receptor and adenylyl cyclase

  19. Hormonal Regulation of Glycogen Synthesis and Degradation • Insulin is secreted from the pancreas (to liver) in response to an increase in blood glucose • Note that the portal vein is the only vein in the body that feeds an organ! • Insulin stimulates glycogen synthesis and inhibits glycogen breakdown • Note other effects of insulin (Figure 23.22)

  20. Hormonal Regulation II Glucagon and epinephrine • Glucagon and epinephrine stimulate glycogen breakdown - opposite effect of insulin! • Glucagon (29 res) is also secreted by pancreas • Glucagon acts in liver and adipose tissue only! • Epinephrine (adrenaline) is released from adrenal glands • Epinephrine acts on liver and muscles • The phosphorylase cascade amplifies the signal!

  21. Epinephrine and Glucagon The difference.... • Both are glycogenolytic but for different reasons! • Epinephrine is the fight or flight hormone • rapidly mobilizes large amounts of energy • Glucagon is for long-term maintenance of steady-state levels of glucose in the blood • activates glycogen breakdown • activates liver gluconeogenesis • Relate these points to sites of action!

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